Melanocortin-1 receptor mutations and pigmentation: Insights from large animals

The melanocortin-1 receptor (MC1R) is a G protein-coupled receptor expressed in cutaneous and hair follicle melanocytes, and plays a central role in coat color determination in vertebrates. Numerous MC1R variants have been identified in diverse species. Some of these variants have been associated with specific hair and skin color phenotypes in humans as well as coat color in animals. Gain-of-function mutations of the MC1R gene cause dominant or partially dominant black/dark coat color, and loss-of-function mutations of the MC1R gene cause recessive or partially recessive red/yellow/pale coat color phenotypes. These have been well documented in a large number of mammals, including human, dog, cattle, horse, sheep, pig, and fox. Higher similarities between large mammals and humans makes them better models to understand pathogenesis of human diseases caused by MC1R mutations. High identities in MC1Rs and similar variants identified in both humans and large mammals also provide an opportunity for receptor structure and function study. In this review, we aim to summarize the naturally occurring mutations of MC1R in humans and large animals.